The long-term goal of this project is the identification of DNA sequence variations which predispose individuals to both alcohol and nicotine dependence. The sequelae of alcohol and nicotine abuse represent major health problems in the US and elsewhere including effects on the development of a variety of cancers, cardiovascular and lung diseases, as well as increasing the risk of suicide and other causes of mortality and morbidity. Many twin, adoption and family studies have demonstrated that there are important genetic contributions to the development of alcoholism and nicotine dependence. More modern studies demonstrate that a substantial proportion of this genetic liability is shared between these two disorders. A variety of physiological, biochemical, lesion and animal model studies have demonstrated the importance of ventral dopaminergic reward mechanisms in the self-administration and reinforcing characteristics of both of these substances. It follows logically, then, that variations in genes involved in the function or formation of these reward pathways may account for a portion or for all of the genetic liability shared by alcohol and nicotine dependence. The goal of the current application is to identify coding region and related DNA sequence variations in candidate genes associated with the dopaminergic reward pathways in individuals who have both nicotine and alcohol dependence. Using denaturing high-performance liquid chromatography (DHPLC) detection of sequence variation and standard and quantitative transmission distortion analytic approaches, three hundred nicotine and alcohol dependent individuals and their parents will be systematically tested for an association between DNA sequence variations in these candidate genes and the presence of alcohol and nicotine dependence. Finding such sequence variations will have important scientific and public health implications for understanding the genetic contributions to the risk for these disorders, for the development of novel pharmacological and other treatment approaches to these disorders and for the identification of individuals at risk for the development of these disorders.